Angewandte
Chemie
Their reaction with 7a afforded 3-substituted phenothiazines
8h–m in yields ranging from 73% to 86% (Table 2, entries 8–
13). Furthermore, the reaction could be scaled up to the gram-
scale without any problems (Table 2, entry 6).
Experimental Section
Typical procedure: An oven-dried Schlenk tube was charged with 2-
iodoaniline 6a (0.5 mmol), CuI (19 mg, 0.1 mmol), l-proline
(11.5 mg, 0.2 mmol), and K2CO3 (2.5 mmol). The tube was evacuated
and backfilled with argon, and then 2-bromobenzenethiol 7a
(0.55 mmol) and 2-methoxyethanol (2.0 mL) were added. The
reaction mixture was stirred at 908C for 24–48 h and then heated to
1108C for 48–72 h. After removal of the solvent in vacuo, the residue
was partitioned between ethyl acetate and water. Extraction work-up
followed by silica gel chromatography gave the desired phenothia-
zine.
2,3-Dimethyl-10H-phenothiazine 8n was obtained from
4,5-dimethyl-2-iodoaniline in 64% yield (Table 2, entry 14).
To further demonstrate the capability of this process for the
elaboration of polysubstituted phenothiazines, we attempted
the coupling reactions between substituted 2-bromobenzene-
thiols and substituted 2-iodoanilines, and were pleased to
isolate 2,8-disubstituted phenothiazines 8o and 8p, the 3,7-
disubstituted phenothiazines 8q, the 1,3-disubstituted pheno-
thiazine 8r, the 6,8-disubstituted phenothiazine 8s, and the
1,3,6,8-tetrisubstituted phenothiazine 8t in satisfactory yields
(Table 2, entries 15–20). These results demonstrated that we
would be able to introduce functional groups at the 1, 2, 3, 6, 7,
and/or 8-positions of the phenothiazine ring by employing
suitable coupling partners. A wide range of functional groups,
such as fluoro, nitro, keto, methoxy, ester, and cyano groups
were well-tolerated under these reaction conditions, which,
along with the ability to decorate the phenothiazine ring at a
variety of positions, makes this process very promising for
synthesizing phenothiazines of great diversity. Importantly, 2-
bromobenzenethiols were essential for this reaction as low
yields were observed when 2-chlorobenzenethiol was used as
the coupling partner.
Received: October 8, 2009
Revised: December 4, 2009
Published online: January 7, 2010
Keywords: copper · cross-coupling · heterocycles ·
.
homogeneous catalysis · phenothiazines
[1] A. Basta-Kaim, B. Budziszewska, L. Jaworska-Feil, M. Tetich,
´
´
[2] A. B. Bate, J. H. Kalin, E. M. Fooksman, E. L. Amorose, C. M.
Price, H. M. Williams, M. J. Rodig, M. O. Mitchell, S. H. Cho, Y.
[3] S. Darvesh, K. V. Darvesh, R. S. McDonald, D. Mataija, R.
[4] K. Kubota, H. Kurebayashi, H. Miyachi, M. Tobe, M. Onishi, Y.
[5] A. Bisi, M. Meli, S. Gobbi, A. Rampa, M. Tolomeo, L.
[6] E. A. Weiss, M. J. Tauber, R. F. Kelley, M. J. Ahrens, M. A.
[8] H.-W. Rhee, S. J. Choi, S. H. Yoo, Y. O. Jang, H. H. Park, R. M.
Pinto, J. C. Cameselle, F. J. Sandoval, S. Roje, K. Han, D. S.
Next, we moved our attention to employing N-substituted
2-iodoanilines to synthesize N-substituted phenothiazines.
The coupling reactions of diamines 10a–10c with 7a worked
well, providing chlorpromazine 11a, triflupromazine 11b, and
acepromazine 11c in 75–81% yields (Scheme 1). These three
compounds are clinically used psychotropic drugs, whilst
chlorpromazine 11a has shown potential for the treatment of
tuberculosis.
Lang, S. Gerber, P. B. Madrid, I. G. Pinto, R. K. Guy, T. L. James,
c) R. Dixit, Y. Dixit, D. C. Gautam, N. Gautam, Phosphorus
Scheme 1. Synthesis of three psychotropic promazine drugs.
[12] For a review, see: H. W. Gschwend, H. R. Rodriguez, Org. React.
1979, 26, 47.
[13] For recent examples, see: a) M. Sailer, A. W. Franz, T. J. J.
haber, A. J. Zucchero, K. I. Hardcastle, T. J. J. Mꢀller, U. H. F.
[14] T. Dahl, C. W. Tornøe, B. Bang-Anderson, P. Nielsen, M.
[15] For selected examples of copper-catalyzed coupling reactions for
the preparation of heterocycles, see: a) R. Martꢂn, R. Rodrꢂguez,
S. L. Buchwald, Angew. Chem. 2006, 118, 7237; Angew. Chem.
Int. Ed. 2006, 45, 7079; b) H. Miyamoto, Y. Okawa, A. Nakazaki,
In conclusion, we have developed a new approach to
construct functionalized phenothiazines, starting from sub-
stituted 2-iodoanilines and 2-bromobenzenethiols, based on a
sequentially controlled CuI/l-proline-catalyzed cascade pro-
cess. The efficiency and substituent tolerance of this proce-
dure have been fully demonstrated by synthesizing a number
of functionalized phenothiazines. Some of these products are
known psychotropic drugs or intermediates for preparing
bioactive compounds. Considering the inexpensive catalytic
system, and the convenient availability of the starting
materials, this method can find numerous applications in
organic synthesis.
Angew. Chem. Int. Ed. 2010, 49, 1291 –1294
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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